Project Summary/Abstract Project Title: New generation EPO peptides with enhanced safety for acute TBI Objectives: Neurodestruction is a key element of the inflammatory cascade that follows acute traumatic brain injury. We hypothesize that this process may be in part immune-mediated. However regardless of precise mechanism, the process can be effectively blocked by our novel small EPO peptides with subsequent improvement in pathology and improved neurologic/neurobehavioral outcome. Of critical importance, our peptides are devoid of severe side effects compared to whole molecule EPO. Specific Aim 1A: Determine the therapeutic effects of our small EPO peptides on acute brain trauma and compare the response to therapy with full-length EPO on modifying the histopathology and clinical outcome in wild-type C57BL/6 mice after traumatic brain injury. Dose-response curves, therapeutic time windows for both i.v. and i.p. therapy, the effect on functional recovery of long term therapy and toxicity will be assessed using PBS sham treated TBI animals as controls. Specific Aim 1B: Determine the therapeutic efficacy and side effect profile of 3 newly described neuroprotective EPO peptides (helix B, aa 58-82) described by Brines et al. (2008) in a head-to- head comparison that span a different domain than our candidate peptides. Specific Aim 1C: Using the same protocol listed for S.A. 1-A, we will assess the neuroprotective effects of our compounds and their safety profile in a second animal species-the Sprague Dawley rat model. Specific Aim 2: Develop a new model for TBI using mice with a transgene coding for GFAP- luciferase. Our library of small EPO peptides will be screened non-invasively in living mice for neuroprotective effects on clinical course and quantitative correlations made between bioluminescence, GFAP-luciferase RT messenger abundance and pathology. Specific Aim 3: We wish to further test our hypothesis by defining the immune system's contribution to the mechanism of tissue injury following TBI. We plan to determine if exogenously administered EPO peptide therapy can favorably modify clinical outcome in RAG1- /- immunodeficient mice compared to whole molecule EPO that have received labeled wild-type T cells/ other immune functional cells by adoptive transfer. Potential Impact on Veterans Health Care: We believe we have generated highly relevant preliminary findings using our patent pending small EPO peptides for neuroprotection that have a much better safety profile than whole molecule EPO therapy. These small unaltered compounds could be in clinical trials in 3 years and our group has the necessary expertise and infrastructure in place for proposing a 4 year research plan with specific aims directed towards treatment of acute traumatic brain injury that could have significant impact on the acute management of battle field and civilian head injuries. Our proposal directly address the VA call for innovative projects for TBI that have the potential to make a significant impact on improving the function of brain injured patients.